Proglucagon, the precursor of glucagon, contains within its sequence two peptide domains related in structure to glucagon. One of these glucagon-like peptides, GLP-I is liberated from proglucagon in the intestinal L cells and the pancreatic islets. The synthetic peptide GLP-I(7-37) has potent insulinotropic actions on pancreatic beta cells at concentrations as low as 10- 11M. The long range goals of this project are to define the role that the newly discovered GLP-I(7-37) peptide has in the regulation of insulin secretion and glucose homeostasis and to determine whether GLP-I(7-37) contributes to the impairment of the beta- cell response to glucose observed in non-insulin dependent diabetes mellitus. The immediate goal is to study the nature of the inteactions of GLP-I(7-37) with the beta-cell. The first part of the project will be an analysis of (i) the binding of GLP-I(7-37) to specific receptor(s) and (ii) the manner in which the binding of GLP-(7-37) is coupled to increases in cellular levels of cAMP. For this purpose we will utilize insulin secreting cell- lines. We will also explore the relative contributions of GLP-I(7- 37) and glucagon to the insulinotropic effect. In particular, we wish to determine whether glucagon acts on the beta-cell in the capacity of an agonist of GLP-I(7-37). In the second part of the project, we will investigate the structural requirements that are necessary for the expression of the biological action of GLP-I(7-37) on beta cells. A selected number of GLP-I(7-37) analogs will be synthesized by the method of solid phase peptide synthesis and their biological potencies measured using both the insulin secreting cell-lines and perfused pancreas preparation. These studies have potential implications for obtaining an understanding of the pathogenesis of non-insulin dependent diabetes mellitus.